Composite biomaterial including anisometric calcium phosphate reinforcement particles and related methods

ABSTRACT

Composite biomaterials (e.g., for use as orthopedic implants), as well as methods of preparing composite biomaterials, are disclosed. The composite biomaterial includes a matrix (e.g., a continuous phase) comprising a thermoplastic, a calcium phosphate composition that is curable in vivo, or combinations thereof. The composite biomaterial also includes an isometric calcium phosphate reinforcement particles which are dispersed within the matrix.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application claims the benefit of U.S. application No.60/179,238, filed on Jan. 31, 2000, which is hereby incorporated in itsentirety by reference.

TECHNICAL FIELD OF THE INVENTION

This invention pertains generally to biomaterials. More particularly,the present invention relates to a composite biomaterial that can beused, for example, as an orthopedic implant.

BACKGROUND OF THE INVENTION

Orthopedic implants are used commonly as structural reinforcements inthe human body. By way of example, orthopedic implants are used tostrengthen failed bone (e.g., broken or deteriorating bone), to stiffencompromised vertebrae, or to eliminate painful arthritic or damagedjoints. Most orthopedic implants presently in use involve the extensiveuse of permanent metal hardware, such as, for example, bone plates andscrews and spine cages.

Despite the enhanced mechanical strength and stiffness associated withthem, such traditional metallic orthopedic implants require invasivesurgical techniques which impose a large degree of surgical trauma,suffering, and rehabilitation time on patients. As an example, thetreatment of hip fractures often requires an incision that is twelveinches or longer. Furthermore, when a stiff metal plate or implant isattached to bone, it tends to “shield” the bone tissue from mechanicalstresses, and, under these conditions, native bone undesirably tends toresorb away.

Nevertheless, finding suitable alternative biomaterials has proven to bedifficult. Particularly, existing non-metal biomaterials have not beensatisfactory, for example, because they are inadequate with respect tomechanical properties (e.g., strength). For example, dense ceramicswould have similar problems because they are stiff, and, thus, arestress shielding, and they have the additional drawback of being brittlesuch that they have a lower fracture toughness. In addition, non-metalbiomaterials, such as, for example, existing polymeric and porousceramic biomaterials are significantly inferior to natural cortical bonein terms of mechanical properties, such as, for example, elasticmodulus, tensile strength, and compressive strength.

By way of example, one alternative approach to the use of metals in thefield of orthopedics involves minimally invasive orthopedic implantsurgical techniques in which injectable bone glue and filler materialsare used (e.g., to repair a bone fracture) instead of metal plates andscrews and the like. As an example, the “skeletal replacement system”(SRS) offered by Norian Corporation (Cupertino Calif.) involves aninjectable cementitious material that cures after injection in the body(i.e., in vivo). However, the SRS material has proven to beunsatisfactory for many load bearing applications because of itsinferior tensile properties and low fracture toughness.

In addition, noteworthy among polymeric materials is the polymethylmethacrylate (PMMA) cement. The PMMA cement also suffers frominsufficient mechanical properties, which, while generally better thanSRS, are still inferior to those of natural cortical bone. In addition,another shortcoming associated with PMMA cement is that a large amountof heat is generated undesirably during the exothermic curing process.The heat generated during the exothermic curing reaction limits thevolume of a bone defect that can be filled inasmuch as a large volume ofbone cement will generate sufficient heat to kill adjacent tissues.Furthermore, PMMA cement also has a tendency to leach out MMA monomerthat can have toxic effects on nearby tissues.

Accordingly, it will be appreciated from the foregoing that there existsa need in the art for a biomaterial (e.g., for orthopedic implants) withdesirable biomechanical properties, as well as methods of preparing suchbiomaterials. It is an object of the present invention to provide such abiomaterial and related methods. These and other objects and advantagesof the present invention, as well as additional inventive features, willbe apparent from the description of the invention provided herein.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a composite biomaterial as well asmethods of preparing composite biomaterials. The composite biomaterialincludes anisometric calcium phosphate reinforcement particles that aredispersed within a matrix. The matrix comprises a thermoplastic polymer,a calcium phosphate composition that is curable in vivo (e.g., in amammal), or any combination thereof.

In another aspect of the present invention, provided is a method ofpreparing a composite biomaterial comprising (a) a matrix including acalcium phosphate composition that is curable in vivo and (b)anisometric calcium phosphate reinforcement particles arranged withinthe matrix. The method comprises providing the anisometric calciumphosphate reinforcement particles. The method also includes preparingthe calcium phosphate composition from at least one calcium-containingcompound and at least one phosphate-containing compound. At least one ofthe calcium-containing compound and phosphate-containing compound isderived by a hydrothermal reaction. In addition, the method comprisescombining the anisometric calcium phosphate reinforcement particles withthe calcium phosphate composition or, alternatively, with at least oneof the calcium-containing compound or phosphate-containing compoundprior to formation of the calcium phosphate composition.

In addition, in another aspect, the present invention provides a methodof preparing a composite biomaterial comprising (a) a matrix including athermoplastic polymer and (b) anisometric calcium phosphatereinforcement particles arranged within the matrix. The method comprisesproviding the anisometric calcium phosphate reinforcement particles andproviding the polymer. The method also includes co-processing thepolymer and the calcium phosphate reinforcement particles to obtain asubstantially uniform mixture thereof. In addition, the method comprisesdeforming and/or densifying the mixture to form the compositebiomaterial.

The invention may best be understood with reference to the accompanyingdrawings and the following detailed description of the preferredembodiments.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic representation of a whisker-shaped anisometricreinforcement particle, in accordance with the present invention.

FIG. 2 is a schematic representation of a platelet-shaped anisometricreinforcement particle, in accordance with the present invention.

FIG. 3 is a schematic representation of a cross-section of a compositebiomaterial, illustrating anisometric reinforcement particles dispersedin a matrix in an aligned manner, in accordance with a preferredembodiment of the present invention.

FIG. 4A illustrates a scanning election microscopy (SEM) micrograph ofconventional calcium hydroxyapatite (HA) powder.

FIG. 4B illustrates an SEM micrograph of HA whiskers.

FIG. 4C illustrates an optical micrograph of high density polyethylene(HDPE) powder.

FIG. 5A illustrates x-ray diffraction patterns (XRD) of HA crystals in ahuman cortical bone (femoral midshaft) specimen.

FIG. 5B illustrates XRD patterns for HA crystals in an exemplarysynthetic HDPE-HA composite that includes 30% by volume HA.

FIG. 6A illustrates Harris texture index measurements of HA crystals ina human cortical bone (femoral midshaft) specimen.

FIG. 6B illustrates Harris texture index measurements of HA crystals inan exemplary synthetic HDPE-HA composite that includes 30% by volume HA.

DETAILED DESCRIPTION OF THE INVENTION

The present invention is predicated, at least in part, on providingcomposite biomaterials that are biocompatible and have desirablebiomechanical properties (e.g., resembling those of natural bone). Thebiomaterials include a matrix (e.g., continuous phase or continuum) of,for example, a thermoplastic polymer, a calcium phosphate composition,or suitable combinations thereof. Significantly, the compositebiomaterials of the present invention also include calcium phosphatereinforcement particles, which are dispersed within the matrix, in orderto provide mechanical reinforcement. In accordance with the presentinvention, the calcium phosphate reinforcement particles are eithersingle crystals or dense polycrystals and are anisometric (as opposed toequiaxed) in nature such that the reinforcement particles exhibitdifferent properties in different orientations or crystallographicdirections. As a result of the anisometric nature of the reinforcementparticles, especially if aligned (as discussed herein below), theinventive composite biomaterials possess enhanced biomechanicalproperties. The composite biomaterials of the present invention havesignificant utility, for example, in mammalian orthopedic implants(e.g., as a prosthesis for replacement of bone).

The matrix can be bioresorbable (i.e., a material capable of beingresorbed by a patient, e.g., a mammal, under normal physiologicalconditions) or non-bioresorbable, as desired. In this respect, in someapplications, it is desirable that the biomaterial be bioresorbable bythe patient, such as, for example, in younger patients where boneregeneration occurs readily. Desirably, in some embodiments,bioresorbable materials are selected so as to be tailored to theparticular patient's own bone regeneration process such that thebioresorbable material would be replaced gradually over time by thepatient's own natural (regenerated) tissue.

In other applications, non-bioresorbability is desirable, e.g., in olderpatients where bone regeneration is retarded, so that the biomaterialremains inert and demonstrates little degradation in biomechanicalproperties. However, the decision of whether to use a bioresorbable ornon-bioresorbable biomaterial depends on many factors including thepatient's health profile, the degree of injury, and the procedurepreferred by the surgeon.

The biomaterial can be percutaneously injected, surgically injected, orsurgically implanted, depending upon the material or materials selectedfor the matrix. By way of example, in embodiments where a major portionof the matrix is a calcium phosphate composition or a thermoplasticpolymer composition that exhibits flowability initially but is capableof curing (setting up) in vivo in a mammalian host after some period oftime, percutaneous or surgical injection (e.g., via a needle, catheter,glue gun or the like) can be utilized to deliver the inventivebiomaterial while in the flowable state to the desired in vivo location.In other embodiments, the initially flowable composition can be curedand formed into a desired shape ex vivo and surgically implanted. Instill other embodiments, for example, where a major portion of thematrix includes a calcium phosphate composition or a thermoplasticpolymer composition where in vivo delivery by injection and/or curing isnot possible or sufficiently limited, the biomaterial can beappropriately shaped by the surgeon and surgically implanted.

Any suitable calcium phosphate composition (e.g., cement) orthermoplastic material, as well as suitable combinations thereof, can beincluded in the matrix. By way of example, and not limitation, examplesof suitable calcium phosphate compounds for inclusion (alone or incombination) in the calcium phosphate composition are listed in Table I.In addition, one or more dopants (e.g., sodium, potassium, magnesium,carbonate, fluoride, chloride, and the like) optionally can be includedin the calcium phosphate composition. If included, the dopantspreferably are included in an amount of less than about 10% by weight ofthe calcium phosphate composition.

TABLE I Exemplary Calcium Phosphate Compounds Abbrev. Chemical FormulaChemical Name Mineral Name ACP Ca_(x)(PO₄)_(y) Amorphous calciumphosphate BCP (Ca₁₀(PO₄)₆OH)_(x) + biphasic calcium (Ca₃(PO₄)₆)_(1-x)phosphate CP calcium phosphate DCP CaHPO₄ dicalcium phosphate MonetiteDCPD CaHPO₄ •2H₂O dicalcium phosphate Brushite dihydrate HA orCa₁₀(PO₄)₆(OH)₂ calcium Apatite or OHAp hydroxyapatite hydroxyapatiteCO₃Ap Ca₁₀(PO₄)₆(OH)₂ carbonated calcium Carbonate with CO₃'shydroxyapatite apatite substituting PO₄'s and/or OH's MCP Ca(H₂PO₄)₂monocalcium phosphate MCPM Ca(H₂(PO₄)₂ •H₂O monocalcium phosphatemonohydrate OCP Ca₈H₂(PO₄)₆ •5H₂O octacalcium phosphate TCP Ca₃(PO₄)₂tricalcium phosphate α-TCP α-Ca₃(PO₄)₂ alpha-tricalcium phosphate β-TCPβ-Ca₃(PO₄)₂ beta-tricalcium phosphate TTCP Ca₄(PO₄)₂O Tetra-calciumHilgenstockite phosphateAs will be appreciated by one skilled in the art, the bioresorbabilityof these calcium phosphate compounds varies according to crystalchemistry.

Referring now to thermoplastic polymers, examples of bioresorbablethermoplastics include, but are not limited to, poly(DL-lactide)(DLPLA), poly(L-lactide) (LPLA), poly(glycolide) (PGA),poly(ε-caprolactone) (PCL), poly(dioxanone) (PDO), poly(glyconate),poly(hydroxybutyrate) (PHB), poly(hydroxyvalerate (PHV),poly(orthoesters), poly(carboxylates), poly(propylene fumarate),poly(phosphates), poly(carbonates), poly(anhydrides),poly(iminocarbonates), poly(phosphazenes), and the like, as well ascopolymers or blends thereof, and combinations thereof.

Examples of non-bioresorbable thermoplastics include, but are notlimited to, polyethylenes, such as high density polyethylene (HDPE),ultra high molecular weight polyethylene (UHMWPE), and low densitypolyethylene (LDPE), as well as polybutylene, polystyrene, polyurethane,polypropylene, polyacrylates, polymethacrylates, such aspolymethylmethacrylate (PMMA), and polymerized monomers such astri(ethylene glycol) dimethacrylate (TEG-DMA), bisphenol a hydroxypropylmethacrylate (bis-GMA), and other monomers listed herein below, and thelike, as well as copolymers or blends thereof and combinations thereof.

In some embodiments, the matrix can include a combination of calciumphosphate compounds, a combination of thermoplastics, or a combinationof one or more calcium phosphate compounds and one or morethermoplastics. Strictly by way of example, in some embodiments, thematrix can include a combination of at least one non-bioresorbablematerial (e.g., thermoplastic or calcium phosphate) and at least onebioresorbable material. For example, the matrix can include at least onecalcium phosphate compound as well as particulate or dissolved (e.g., inwater or other suitable biocompatible medium) thermoplastic.

Desirably, in some embodiments in which the matrix includes acombination of a non-bioresorbable material and a bioresorbablematerial, the matrix can be arranged so that the concentration of thebioresorbable component is higher at or near the matrix surface. In thisrespect, the bioresorbable component can be graded from the matrixsurface to the inner core of the matrix.

With respect to the reinforcement particles, the particular calciumphosphate utilized for the reinforcement particles can be selected, forexample, from the list in Table I, as well as combinations thereof.Dopants or other additives can be included within the reinforcementparticles, if desired. In accordance with the present invention, thecalcium phosphate reinforcement particles are in the form of singlecrystals or dense polycrystals, and are anisometric in nature. Forexample, the calcium phosphate reinforcement particles 10 can be in theshape of whiskers 12, as shown in FIG. 1, or in the shape of platelets14, as shown in FIG. 2. In particular, the reinforcement particles arecharacterized as having a c-axis 16, which is the longest othogonalaxis, and an a-axis 18, which is the shortest othogonal axis, as shownin FIGS. 1 and 2. Pursuant to the present invention, inasmuch as thereinforcement particles are anisometric (and not equiaxed), therespective lengths along the c-axis and the a-axis are different. Inthis respect, the reinforcement particles of the present invention arecharacterized as having a mean aspect ratio (length along c-axis/lengthalong a-axis) of greater than 1 and less than 100. Preferably, the meanaspect ratio of the reinforcement particles is from about 5 to about 50,more preferably, from about 7.5 to about 35, and still more preferably,from about 10 to about 20.

The reinforcement particles can be of any suitable size. For example, insome embodiments, the reinforcement particles have mean dimensions offrom about 1 micrometer to about 500 micrometers along the c-axis andfrom about 0.02 micrometers to about 20 micrometers along the a-axis.Other exemplary mean dimensions include a length of from about 5micrometers to about 50 micrometers along the c-axis and a length offrom about 0.1 micrometer to about 10 micrometers along the a-axis.Additional exemplary mean dimensions include a length of from about 10micrometers to about 40 micrometers along the c-axis and a length offrom about 0.2 micrometers to about 8 micrometers along the a-axis.

In addition, some smaller, (e.g., nano-sized) calcium phosphatereinforcement particles can be included as well. For example, thenano-sized (e.g., mean dimensions of from about 1 nanometers to about500 nanometers) can be in the form of bioresorbable particles, in whichcase the smaller size would be advantageous because resorption wouldoccur more readily. Desirably, if present, the nano-sized reinforcementparticles are concentrated more heavily at or near the matrix surface.In particular, if present, the nano-sized calcium phosphatereinforcement particles preferably are graded from the matrix surface tothe inner core of the matrix.

The reinforcement particles can be included in any suitable amount inthe inventive composite biomaterial. For example, the reinforcementparticles can be provided in an amount of from about 1% by volume of thecomposite biomaterial to about 60% by volume of the compositebiomaterial, more preferably, from about 30% by volume of the compositeto about 60% by volume of the composite, still more preferably, fromabout 40% by volume of the composite to about 60% by volume of thecomposite.

Notably, the calcium phosphate reinforcement particles providemechanical reinforcement (e.g., strength and/or fracture toughness), forexample, because of their anisometric morphology and because of theirnature as single-crystals or dense polycrystals which have greaterinherent mechanical properties as compared to the matrix. With respectto morphology, because the reinforcement particles geometrically areanisometric, the particles effectively reinforce the biomaterial.Particularly, the anisometric reinforcement particles 10 can be providedso that they are dispersed in the matrix 20, preferably so that there isoverlap between particles, as seen in FIG. 3, so that reinforcement isenhanced. For purposes of clarity, the term “dispersed” does notpreclude some contact between particles.

The reinforcement particles can be randomly oriented (i.e., unaligned)in some embodiments. However, as seen in FIG. 3, the reinforcementparticles 10 preferably are predominately aligned within the matrix 20.Crystallographic or morphological alignment (e.g., a preferredorientation) of the reinforcement particles within the matrix 20 resultsin anisotropy for the overall composite 22. By way of contrast, if thereinforcement particles are randomly oriented (i.e., no preferredorientation) within the matrix, the overall composite possessesisotropic properties. Composites exhibiting anisotropic properties, thatis, having different properties in different directions of thecomposite, possess enhanced mechanical properties in one or twodirections of the composite over composites exhibiting isotropicproperties, that is, having equal properties in all directions, all elsebeing equal. In many cases (for example, the long shaft of the femur),the unique mechanical properties possessed by native human bone are dueto anisotropy.

As used herein, the term “aligned” reinforcements will be understood bythose of ordinary skill in the art as a preferred crystallographic ormorphological orientation. The preferred orientation or texture of amaterial is most accurately measured quantitatively by way of anorientation distribution function (ODF). An ODF can be measured usingx-ray diffraction pole figure analysis and/or stereological analysis, asdescribed by Sandlin et al., “Texture Measurement on MaterialsContaining Platelets Using Stereology,” J. Am. Ceram. Soc., 77 [8]2127-2131 (1994). In these quantitative techniques, a random ODF isassigned a value of 1, such that values greater than 1 indicate apreferred (aligned) orientation in multiples of a random distribution(MRD). In accordance with preferred embodiments of the invention, thereinforcement particles are aligned in the matrix such that they have anODF pursuant to this quantitative technique of greater than 1 MRD, morepreferably, an ODF of at least about 2 MRD, even more preferably an ODFof at least about 3 MRD, still more preferably, an ODF of at least about4 MRD, even more preferably an ODF of at least about 5 MRD, e.g., an ODFof from about 5-20 MRD, which approximately corresponds to that of thehuman femur. In some embodiments, it is desirable to have an even higherODF, for example, an ODF of at least about 20, to achieve mechanicalanisotropy in the synthetic composite biomaterial that matches thehost's bone material

As will be appreciated by those of ordinary skill in the art,semi-quantitative techniques of identifying the preferred (aligned)orientation or texture of a material are described by Harris (see, e.g.,“Quantitative Measurement of Preferred Orientation in Rolled UraniumBars,” Phil. Mag. 43 [336] 113-123 (1952); and Peterson et al., “X-RayTexture Analysis of Oriented PZT Thin Films,” Mat. Res. Joc. Symp.Proc., 433, 297-302 (1996)) and Lotgering (see, e.g., “TopotacticalReactions with Ferrimagnetic Oxides Having Hexagonal CrystalStructures—I,” J. Inorg. Nucl. Chem., 9, 113-123 (1959)). It will beappreciated that under the Harris technique, a random orientation alsois assigned a value of 1, while in the Lotgering technique, the randomorientation is assigned a value of zero. Thus, a preferred, or aligned,orientation would have a volume greater than 1 or zero, respectively,under these semi-quantitative techniques.

In addition to their morphology, the inherent strength of thereinforcement particles, which is greater than that of the matrix,enhances the mechanical strength of the composite. In this respect,whereas the matrix can include a porous material of polycrystals (e.g.,cement), the reinforcement particles are not porous and are unitarycrystals. The porosity of the matrix is biologically advantageous butundesirable with respect to mechanical strength. Accordingly, thereinforcement particles enhance the mechanical strength of the compositebiomaterial of the present invention.

The inventive composite biomaterial optionally can include additives, ifdesired. By way of example, the biomaterial can include one or moresurface-active agents in order to enhance interfacial bonding betweenthe reinforcement particles and the matrix. As other examples, theinventive biomaterial can include one or more growth factors, including,but not limited to, those in the TGF-beta super family (e.g., TGF-betas,bone morphogenic proteins, such as, for example, BMP-2, BMP-7 or thelike, etc.), fibroblast growth factors, epidermal growth factors,vascular endothelial growth factors, insulin-like growth factors, orinterleukins, to enhance osteoinductivity and/or bone regeneration.Furthermore, the inventive biomaterial can include one or moretranscription factors or matrix metalloproteinases to improve boneregeneration, or speed resporption and replacement of the biomaterial.In addition, the biomaterial can be coated with one or more peptides orproteins that enhance attachment of bone cells (e.g., osteopontin,integrins, matrix receptors, RGD, or the like).

The anisometric calcium phosphate particles can be prepared in anysuitable manner. Suitable techniques are described, for example, in U.S.Pat. No. 5,227,147; Fujishiro et al., “Preparation of Needle-likeHydroxyapatite by Homogeneous Precipitation under HydrothermalConditions,” J. Chem. Technol. Biotechnol., 57, 349-353 (1993);Yoshimura et al. “Hydrothermal Synthesis of Biocompatible Whiskers,” J.Mater. Sci., 29, 3399-3402 (1994); Suchanek et al., “BiocompatibleWhiskers with Controlled Morphology and Stoichiometry,” J. Mater. Res.,10 [3] 521-529 (1995); Kandori et al., “Texture and Formation Mechanismof Fibrous Calcium Hydroxyapatite Particles Prepared by Decomposition ofCalcium-EDTA Chelates,” J. Am. Ceram. Soc., 80 [5] 1157-1164 (1997);Nakahira et al., “Novel Synthesis Method of Hydroxyapatite Whiskers byHydrolysis of α-Tricalcium Phosphate in Mixtures of Water and OrganicSolvent,” J. Am. Ceram. Soc., 82 [8] 2029-2032 (1999); and Katsuki etal., “Microwave-Versus Conventional-Hydrothermal Synthesis ofHydroxyapatite Crystals from Gypsum,” J. Am. Ceram. Soc., 82 [8]2257-2259 (1999).

In some embodiments, the reinforcement particles can be produced by wayof a hydrothermal reaction, e.g., at low temperatures (such as, forexample, from about 37° C. to about 200° C.) from chemical solutionscontaining chemical reactant precursors, pH modifying precursors, and/orchelating acids. In particular, the reactant precursors can be in theform of a calcium-containing compound and a phosphate-containingcompound, both of which are selected such that they exhibit greatersolubility in water than the solubility in water of thecalcium-containing reinforcement particles desired to be produced (e.g.,via precipitation or ion exchange in solution). Examples of suchcalcium-containing compounds include, but are not limited to, thecompounds listed in Table I, as well as calcium hydroxide, calciumnitrate, calcium chloride, calcium carbonate, calcium lactate, calciumacetate, calcium citrate, calcium sulfate, calcium fluoride, calciumoxalate, and the like, as well as combinations thereof. Examples ofphosphate-containing compounds include, but are not limited to, thecompounds listed in Table I, as well as phosphoric acid,fluorophosphoric acid, sodium orthophosphate, potassium orthophosphate,ammonium orthophosphate, and the like, as well as combinations thereof.It will be appreciated that pH modifying precursors can include anysuitable acid or base. Chelating acids can include, for example, formicacid, acetic acid, lactic acid, valeric acid, ethylenediaminetetraceticacid (EDTA), glycolic acid, oxalic acid, citric acid, and the like, aswell as combinations thereof.

Producing the reinforcement particles hydrothermally is desirablebecause the size and morphology of the resulting reinforcement particlescan be controlled readily, for example, by adjusting the reactantconcentrations solution pH, type of chelating acid, reaction heatingrate, mixing reaction temperature, and length of reaction. Reactiontemperatures, for example, greater than 100° C., are especiallyconducive to whisker formation. It is to be noted, however, thatreactions at temperatures greater than 100° C. require a pressure vesselthat is suitably lined (e.g., with TEFLON®) to contain the pressurizedaqueous solution.

Turning now to the preparation of the composite biomaterials, a matrixincluding at least one calcium phosphate composition (that is curable invivo) can be prepared from one or more calcium-containing and one ormore phosphate-containing reactant compounds. Notably, at least one ofthe calcium-containing or phosphate-containing reactant compounds isderived by a hydrothermal reaction. In some embodiments, both thecalcium-containing and phosphate-containing reactant compounds arederived hydrothermally.

Particularly, by utilizing a hydrothermal reaction to derive at leastone of the calcium-containing and phosphate-containing reactantcompounds, the resultant reactant compounds can be produced so as tohave a very fine size and controlled purity. Preferably, at least one ofthe calcium-containing and phosphate-containing reactant compounds ischaracterized by particles having a mean diameter of less than about 1micrometer, more preferably, a mean diameter of from about 1 nanometerto about 500 nanometers, even more preferably, from about 1 nanometer toabout 100 nanometers. By starting with a smaller grain size for one orboth of the calcium-containing and phosphate containing reactantcompounds, the resulting calcium phosphate matrix composition also wouldbe in the form of smaller particles (e.g. polycrystals). The smallersize of the particles of the calcium phosphate matrix compositionresults in a matrix of enhanced mechanical strength.

The calcium-containing and phosphate-containing reactant compounds canbe selected, for example, from the respective lists ofcalcium-containing and phosphate-containing chemical precursorsdiscussed herein above with respect to the reinforcement particles. Toproduce the calcium phosphate matrix composition, the calcium-containingand phosphate-containing reactant compounds can be mixed, for example,while dry (e.g., in powder form). In some embodiments, the powders canbe mixed with phosphoric acid crystals and ground with mortar andpestle. In addition, as an example, a sodium phosphate solution can beadded to form a flowable paste, which is injectable into a patient andwhich is capable of curing in vivo in a mammalian host after injectionat the desired locus (e.g., bone, such as the femur or vertebrae). Inthis respect, the paste desirably is formed, for example, in theoperating room, shortly before delivery (e.g., by injection) into thepatient where it can then harden in vivo. In other embodiments, thecompounds can be prepared in two separate flowable pastes which can bestored separately, and later mixed together and injected at the desiredlocus where it can harden in vivo.

The calcium phosphate reinforcement particles can be added prior toformation of the calcium phosphate composition (e.g., added to one orboth of the calcium-containing compound(s) and phosphate-containingcompound(s)) and/or after the calcium phosphate composition is formed.

With respect to the preparation of a composite biomaterial comprising amatrix that includes at least one thermoplastic polymer, a substantiallyuniform mixture of polymer and calcium phosphate reinforcement particlesis formed via co-processing. By way of example, in some embodiments, apreform is made from polymer provided in the form of particles. Thepolymer particles can be produced in any suitable manner. For example,the polymer can be dissolved in any suitable solvent in which thepolymer can be dissolved (e.g., water, xylene, chloroform, toluene,methylene chloride, tetrahydrofuran, ethyl acetate,hexafluoroisopropanol, acetone, alcohols, and the like). In suchembodiments, the polymer particles can be formed by precipitation orgelation from the solution, for example, under rapid mixing. The solventis then removed, e.g., by vacuum oven drying, distillation andcollection, freeze drying, and the like. Additionally, the polymerparticles and/or gel may be suspended in a suitable medium (e.g., water,alcohols, and the like) and homogenized by high shear mixing to providea uniform distribution of particles or repeatedly washed to removeresidual traces of the solvent. The polymer particles and the calciumphosphate reinforcement particles each are suspended in a suitablemedium for dispersing the particles, (e.g., water, alcohols, and thelike). The preform is then formed by wet co-consolidation of the polymerand calcium phosphate particulate suspension.

In other embodiments, a preform is formed from a polymer foam, e.g.,having open porosity (e.g., continuous). The polymer foam can beprovided in a similar manner to the preparation of the polymerparticles, but while dissolving the polymer at a slower mixing rate,with slower solvent removal, and at a higher fraction of polymerrelative to solvent. Thus, the polymer foam is formed by dissolving thepolymer in solvent (e.g., water, xylene, chloroform, toluene, methylenechloride, tetrahydrofuran, ethyl acetate, hexafluoroisopropanol,acetone, alcohols, and the like) while mixing followed by precipitationor gelation from the solution, followed by solvent removal via vacuumoven drying, distillation and collection, freeze drying, and the like.Additionally, the polymer foam and/or gel may be suspended in a suitablemedium (e.g., water, alcohols, and the like) and repeatedly washed toremove residual traces of the solvent. In these embodiments, theco-processing includes infiltrating the polymer foam with a suspension(e.g., alcohols, in water and the like) of the calcium phosphateparticles, so as to form the preform.

In still other embodiments, a preform is formed from a porous compact ofthe calcium phosphate reinforcement particles. The thermoplastic polymeris provided and infiltrated into the porous calcium phosphate compact.By way of example, the polymer can be provided molten, solvated (e.g.,in a biocompatible medium, such as water or other medium that dissolvesthe thermoplastic), or as a polymerizing mixture comprising monomer,initiator, and, optionally, polymer powder and/or co-initiators (asdiscussed herein below). By way of example, the porous compact of thecalcium phosphate reinforcement particles is produced, for example, bydry pressing the calcium phosphate particles and sintering (e.g., attemperatures of from about 600° C. to about 1000° C.) the dry pressedparticles to form the compact. In the co-processing, the porous compactof the calcium phosphate reinforcement particles is infiltrated with thepolymer.

Once the preform is formed, it is thermo-mechanically densified anddeformed to form the composite biomaterial. By way of example, thepreform can be thermo-mechanically densified and deformed via channeldie forging, injection molding, extrusion, pultrusion, or the like. Inaddition, the thermo-mechanical deformation and densification desirablycan include aligning the calcium phosphate reinforcement particlesmorphologically and/or crystallographically. The composite can bedelivered to the patient, for example, by way of surgical implantation.

In still further embodiments, where a major portion of the matrix is athermoplastic polymer composition and the composite biomaterial is to bedelivered by either percutaneous or surgical injection, thethermoplastic polymer matrix may also be provided by mixing combinationsof polymer powders and monomers with the addition of initiators andco-initiators (e.g., benzoyl peroxide, dimethylaniline, ascorbic acid,cumene hydroperoxide, tributylborane, sulfinic acid, 4-cyanovalericacid, potassium persulfate, dimethoxybenzoine, benzoic-acid-phenylester,N,N-dimethyl p-toluidine, dihydroxy-ethyl-p-toluidine, and the like, andcombinations thereof) to induce polymerization and hardening in-situduring composite co-processing. Exemplary monomers include, but are notlimited to, acrylic monomers such as, for example, methylmethacrylate(MMA), 2,2′-bis(methacryloylethoxyphenyl) propane (bis-MEEP), bisphenola polyethylene glycol diether dimethacrylate (bis-EMA), urethanedimethacrylate (UDMA), diphenyloxymethacrylate (DPMA),n-butylmethacrylate, tri(ethylene glycol) dimethacrylate (TEG-DMA),bisphenol a hydroxypropylmethacrylate (bis-GMA), and the like, andcombinations thereof. Additionally, stabilizers (e.g., hydroquinone,2-hydroxy-4-methoxy-benzophenone, and the like, and combinationsthereof) may be added to mixtures to prevent premature polymerization ofthe monomers. The calcium phosphate reinforcements may be provided andmixed into any part of the polymer mixture prior to, during or after thepolymer mixture is formed, yielding a flowable, polymerizing compositebiomaterial. Additionally, the polymer and or composite mixture may bemixed under vacuum or centrifuged to minimize porosity caused byentrapped gases. The polymer mixture is viscous in nature and graduallyhardens (or “cures”) as polymerization progresses. Thus, prior tohardening, the composite biomaterial may be shaped and/or delivered bymeans of viscous flow, including such processes as percutaneous orsurgical injection, channel die forging, compression molding, injectionmolding, extrusion, or the like. In addition, mechanical deformationduring viscous flow desirably can include aligning the calcium phosphatereinforcement particles morphologically and/or crystallographically. Oneskilled in the art will recognize that the desired shape of the implantmay be formed ex vivo by mechanical deformation prior to hardening, byshaping or machining a bulk block of the biomaterial after hardening, orby either percutaneous or surgical injection of the biomaterial to thedesired locus where it will harden in vivo.

The following examples further illustrate the present invention but, ofcourse, should not be construed as in any way limiting its scope.

Examples 1-4 Exemplary HA Whisker Syntheses

These examples demonstrate the preparation of exemplary calciumphosphate, namely calcium hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂),reinforcement particles in the shape of “whiskers” with varied size andshape.

Homogeneous solutions containing 0.015M P, 0.025M Ca and 0.050Mchelating acid were prepared. For each solution, 1.725 g of H₃PO₄ and achelating acid were first added to 1000 ml distilled, de-ionized waterunder moderate stirring at room temperature, before dissolving 1.853 gCa(OH)₂. The chelating acid was used to chelate Ca ions in solution andincluded one of the following: 5.124 g DL-lactic acid (CH₃CHOHCO₂H),2.302 g formic acid (HCO₂H), 3.003 g glacial acetic acid (CH₃CO₂H), or5.110 g valeric acid (CH₃(CH₂)₃CO₂H), which correspond to examples 1-4,respectively. Each solution was sealed to prevent evaporation andcontinuously stirred until the dissolution of Ca(OH)₂ was determined tobe complete upon visual inspection (typically after 2 h). Solutions werethen filtered, measured for pH, and stored in bottles purged withnitrogen gas. Each solution had pH=4. If necessary, HNO₃ or NH₄OH wereadded to achieve this pH.

HA whiskers were grown by precipitation from the homogenous reactionsolutions in a PTFE-lined stainless steel pressure vessel. The vesselwas filled with a 100 ml aliquot of the reaction solution, purged withnitrogen gas, and sealed. The reactor was heated by placing the entirevessel into an oven equilibrated at the desired reaction temperature.The temperature inside the reactor was measured with time by athermocouple placed inside the TEFLON® liner and was shown toasymptotically reached the ambient oven temperature. The reaction washeld at a final temperature of 200° C. for 2 h (8 h total).

After reaction, the pressure vessel was removed from the oven and cooledto less than 100° C. within 1 h using a water-cooled aluminum block andmotorized fan. Precipitates were filtered from the supernatant solutionusing a Büchner funnel and washed under a continuous flow of 100 mldistilled, de-ionized water. The filtrate was placed in a petri dish anddried in an oven at 80° C. for at least 12 h.

The precipitate was identified as calcium hydroxyapatite by x-raydiffraction (XRD). The particle dimensions and whisker morphology of theprecipitates was observed by optical microscopy and quantitativelymeasured using stereological techniques (Table 2).

TABLE 2 Average Size and Shape Measured for the HA Whiskers SynthesizedChelating avg. length avg. width avg. aspect Example Acid (μm) (μm)ratio 1 DL-lactic 22.3 2.4 9.5 acid 2 formic acid 19.3 2.3 8.7 3 aceticacid 25.9 2.5 10.7 4 valeric acid 43.1 4.3 11.3

Example 5 Exemplary HA-HDPE Composites

This example demonstrates the preparation of an exemplary high densitypolyethylene (HDPE) matrix reinforced with calcium phosphate, namelycalcium hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂), reinforcement particles in theshape of “whiskers”. For comparison, specimens were made from the HDPEpolymer matrix alone as well as the HDPE polymer matrix reinforced witha conventional, equiaxed HA powder using the same processing technique.

HA whiskers were grown by precipitation from a homogenous aqueoussolution (similar to example 1), containing 0.05 M Ca(OH)₂, 0.03 MH₃PO₄, and 0.10 M lactic acid, in a TEFLON® lined stainless steelpressure vessel at 200° C. for 4 h. HDPE powder was prepared bydissolving commercially available HDPE pellets in boiling xylene,cooling the solution to form a gel, extracting the solvent, andhomogenizing the precipitated polymer in ethanol.

The appropriate amounts of HDPE and HA powders were ultrasonicallydispersed in ethanol at a solids loading of 13 vol %. The suspension wasvacuum filtered in a 10 mm diameter mold to form a porous cylindricalcomposite preform. After drying, the preform was subsequently pressed ina 10 mm vacuum pellet die to 280 MPa at 25° C. and again at 145° C.Apparent densities of greater than 97% were typically achieved. Thedensified preform was then placed vertically into a channel die forgeand bilaterally extruded at 145° C. into a 2.5×10×120 mm flat bar, fromwhich ASTM D638 type V tensile bars were machined. Tensile tests wereperformed under atmospheric conditions and a displacement rate of 5mm/min.

The degree of preferred crystallographic orientation was determined byx-ray diffraction (XRD). For comparison, human cortical bone specimenswere taken from the proximal end of the femoral midshaft. Thick sectionswere deproteinized by soaking 72 h in 7% NaOCl. The Harris texture index(see, e.g., Harris and Peterson articles, supra) was used tosemi-quantitatively measure the degree of preferred crystallographicorientation (see discussion herein above).

The particle size and morphology of all starting powders were observedby scanning electron microscopy (SEM), and are shown in FIGS. 4A-4C,respectively. The conventional HA (FIG. 4A) was equiaxed and sphericalwith an average particle size of 2-3 μm. The whiskers (FIG. 4B) were onaverage 20 μm in length with an average aspect ratio of 10. Note thatthe [002] crystallographic axis lies along the whisker length. The HDPEpowder particles (FIG. 4C) were spherical and 10-30 μm in diameter.

XRD patterns for human cortical bone specimens and an exemplarycomposite are shown in FIGS. 5A and 5B. In both cases, the (002) peakshave a higher relative intensity on the longitudinal cross-sections(second pattern from top) than on the perpendicular cross-sections (thepatterns above and below). Thus, HA crystals in both specimens have apreferred orientation in the longitudinal directions (vertical in theschematics). Harris texture index measurements provided asemi-quantitative estimate the degree of preferred orientation and areshown in FIGS. 6A and 6B. As will be appreciated by those of ordinaryskill in the art, in FIGS. 6A and 6B, “hkl” corresponds to the Millerindices of specific crystallographic planes of the HA reinforcementparticles. It is to be noted that each crystallographic plane listed inFIG. 6 (002, 210, 300) corresponds to a specific XRD peak in FIG. 5. Italso is to be noted that a value of 1.0 corresponds to a randomorientation distribution. Under the given processing conditions, aslightly higher but similar degree of preferred orientation was achievedin the synthetic composite compared to cortical bone. The preferredorientation in bone is known to be physiological in origin. In theHDPE-HA composite, whisker alignment was induced by shear stressesoccurring along the flow field as the material extruded in the forgemold.

Mechanical tests demonstrated the improved mechanical properties of theHA whisker reinforced composites compared to the matrix alone as well asreinforcement with a conventional HA powder (Table 3). The enhancedmechanical properties over the conventional HA powder are attributed tothe anisometric morphology of the whisker reinforcements and theirpreferred orientation (“alignment”) along the direction of appliedstress.

TABLE 3 Mechanical Properties of the Composites in Example 5Reinforcement Ultimate Tensile Tensile vol % HA Phase Strength (MPa)Modulus (GPa)  0 none 27 1.1 10 conventional 27 2.2 HA 10 HA whiskers 272.5 30 conventional 23 5.3 HA 30 HA whiskers 28 6.5

Example 6 Exemplary HA-PMMA Bone Cement Composites

This example demonstrates the preparation of an exemplarypoly(methylmethacrylate) (PMMA) matrix reinforced with calciumphosphate, namely calcium hydroxyapatite (Ca₁₀(PO₄)₆(OH)₂),reinforcement particles in the shape of “whiskers”. For comparison,specimens were made from the PMMA polymer matrix alone as well as thePMMA polymer matrix reinforced with a conventional, equiaxed HA powderusing the same processing technique.

HA whiskers were grown by precipitation from a homogenous aqueoussolution (similar to example 1), containing 0.05 M Ca(OH)₂, 0.03 MH₃PO₄, and 0.10 M lactic acid, in a Teflon lined stainless steelpressure vessel at 200° C. for 2 h. A commercially available PMMA bonecement, Simplex P™ (Howmedica), was mixed according to manufacturerrecommendations using a vacuum stirring bowl. However, the monomer andpowder ratios were adjusted to accommodate incorporating varying volumefractions of the HA reinforcements. Prior to reaching the “dough” stage,the bone cements were added to a syringe and injected into ASTM D638type V tensile specimen mold or into ASTM F571 compression specimenmolds. All tests were performed under atmospheric conditions and adisplacement rate of 5 mm/min.

The particle size and morphology of the HA reinforcement powders wereobserved by scanning electron microscopy (SEM), and are shown in FIG. 5.The conventional HA was equiaxed and spherical with an average particlesize of 2-3 μm. The whiskers were on average 20 μm in length with anaverage aspect ratio of 10. Note that the [002] crystallographic axislies along the whisker length.

Mechanical tests demonstrated the improved mechanical properties of theHA whisker reinforced composites compared to the matrix alone as well asreinforcement with a conventional HA powder (Table 4). The enhancedmechanical properties over the conventional HA powder are attributed tothe anisometric morphology of the whisker reinforcements and theirpreferred orientation (“alignment”) along the direction of appliedstress. Shear stresses caused by material flow during injectiondeveloped a preferred crystallographic orientation of the HA whiskerswithin the matrix material and yielded anisotropic mechanicalproperties. The degree of preferred orientation in HA whisker reinforcedspecimens, like example 5, was similar to that measured in humancortical bone.

TABLE 4 Mechanical Properties of the Composites in Example 6. UltimateUltimate Tensile Tensile Compressive vol % Reinforcement StrengthModulus Strength HA Phase (MPa) (GPa) (MPa)  0 none 37 3.0 129 10conventional 23 3.5 117 HA 10 HA whiskers 27 4.3 125

All of the references cited herein, including patents, patentapplications, and publications, are hereby incorporated in theirentireties by reference.

While this invention has been described with an emphasis upon preferredembodiments, it will be obvious to those of ordinary skill in the artthat variations of the preferred embodiments may be used and that it isintended that the invention may be practiced otherwise than asspecifically described herein. Accordingly, this invention includes allmodifications encompassed within the spirit and scope of the inventionas defined by the following claims.

1. A composite biomaterial comprising: (a) a matrix including (i) acalcium phosphate composition that can cure in vivo, (ii) athermoplastic polymer, or (iii) any combination of (i) and/or (ii); and(b) anisometric calcium phosphate reinforcement particles dispersedwithin the matrix, wherein the reinforcement particles are alignedwithin the matrix and are present in an amount of from about 1% byvolume of the composite to about 60% by volume of the composite, andwherein the reinforcement particles have a mean aspect ratio (lengthalong c-axis/length along a-axis) of greater than 1 and less than 100.2. The composite of claim 1, wherein the mean aspect ratio is from about5 to about
 50. 3. The composite of claim 2, wherein the mean aspectratio is from about 10 to about
 20. 4. The composite of claim 1, whereinat least some of the reinforcement particles are shaped like whiskers.5. The composite of claim 1, wherein at least some of the reinforcementparticles are shaped like platelets.
 6. The composite of claim 1,wherein the reinforcement particles are present in an amount of fromabout 40% by volume of the composite to about 60% by volume of thecomposite.
 7. The composite of claim 1, wherein the reinforcementparticles have dimensions of from about 1 micrometer to about 500micrometers along the c-axis and from about 0.02 micrometers to about 20micrometers along the a-axis.
 8. The composite of claim 7, wherein thereinforcement particles have a length of from about 5 micrometers toabout 50 micrometers along the c-axis and from about 0.1 micrometers toabout 10 micrometers along the a-axis.
 9. The composite of claim 1,wherein the matrix includes at least one thermoplastic that isnon-bioresorbable.
 10. The composite of claim 9, wherein thenon-bioresorbable thermoplastic is selected from the group consisting ofpolyethylene, high density polyethylene (HDPE), ultra high molecularweight polyethylene (UHMWPE), low density polyethylene (LDPE),polybutylene, polystyrene, polyurethane, polyacrylates,polymethacrylates, polypropylene, copolymers thereof, and blendsthereof.
 11. The composite of claim 1, wherein the matrix includes atleast one thermoplastic that is bioresorbable.
 12. The composite ofclaim 11, wherein the bioresorbable thermoplastic is selected from thegroup consisting of poly(DL-lactide) (DLPLA), poly(L-lactide) (LPLA),poly(glycolide) (PGA), poly(e-caprolactone) (PCL), poly(dioxanone)(PDO), poly(glyconate), poly(hydroxybutyrate) (PHB),poly(hydroxyvalerate (PHV), poly(orthoesters), poly(carboxylates),poly(propylene fumarate), poly(phosphates), poly(carbonates),poly(anhydrides), poly(iminocarbonates), poly(phosphazenes), copolymersor blends thereof, and combinations thereof.
 13. The composite of claim1, wherein the composite includes at least one non-bioresorbablethermoplastic and at least one bioresorbable thermoplastic.
 14. Thecomposite of claim 13, wherein the bioresorbable thermoplastic is gradedfrom a surface of the matrix to an inner core of the matrix.
 15. Thecomposite of claim 1, wherein the matrix includes at least one calciumphosphate compound.
 16. The composite of claim 15, wherein the matrixincludes particulate or dissolved bioresorbable or non-bioresorbablethermoplastic.
 17. The composite of claim 1, wherein at least some ofthe reinforcement particles are bioresorbable.
 18. The composite ofclaim 17, wherein the bioresorbable reinforcement particles are gradedfrom a surface of the matrix to an inner core of the matrix.
 19. Thecomposite of claim 1, wherein the matrix includes the calcium phosphatecomposition, and wherein the calcium phosphate composition is selectedfrom the group consisting of amorphous calcium phosphate, biphasiccalcium phosphate, calcium phosphate, dicalcium phosphate, dicalciumphosphate dihydrate, calcium hydroxyapatite, carbonated calciumhydroxyapatite, monocalcium phosphate, monocalcium phosphatemonohydrate, octacalcium phosphate, tricalcium phosphate,alpha-tricalcium phosphate, beta-tricalcium phosphate, tetracalciumphosphate, and combinations thereof.
 20. The composite of claim 19,wherein the calcium phosphate composition includes at least one dopant.21. The composite of claim 1, wherein the anisometric calcium phosphatereinforcement particles are selected from the group consisting ofamorphous calcium phosphate, biphasic calcium phosphate, calciumphosphate, dicalcium phosphate, dicalcium phosphate dihydrate, calciumhydroxyapatite, carbonated calcium hydroxyapatite, monocalciumphosphate, monocalcium phosphate monohydrate, octacalcium phosphate,tricalcium phosphate, alpha-tricalcium phosphate, beta-tricalciumphosphate, tetracalcium phosphate, and combinations thereof.
 22. Thecomposite of claim 21, wherein at least some of the anisometric calciumphosphate reinforcement particles include at least one dopant.
 23. Thecomposite of claim 1, further comprising at least one surface-activeagent.
 24. The composite of claim 1, further comprising at least oneadditive selected from the group consisting of growth factors,transcription factors, matrix metalloproteinases, peptides, proteins,and combinations thereof.
 25. A prosthesis for replacement of bonecomprising the composite of claim
 1. 26. A method of preparing thecomposite biomaterial of claim 1, the biomaterial comprising: (a) amatrix including at least one thermoplastic polymer and (b) anisometriccalcium phosphate reinforcement particles arranged within the matrix,said method comprising: providing the anisometric calcium phosphatereinforcement particles; providing the polymer; co-processing thepolymer and the calcium phosphate reinforcement particles to obtain asubstantially uniform mixture thereof; and thermo-mechanically ormechanically deforming and/or densifying the mixture to faun thecomposite biomaterial.
 27. The method of claim 26, wherein theanisometric calcium phosphate reinforcement particles are provided via ahydrothermal reaction.
 28. The method of claim 26, wherein saidproviding the polymer includes providing particles of the polymer in afirst suspension, wherein said providing the anisometric calciumphosphate reinforcement particles includes providing the reinforcementparticles (a) in the first suspension or (b) in a second suspension, andwherein said co-processing the polymer and the calcium phosphatereinforcement particles to obtain a substantially uniform mixturethereof comprises wet co-consolidating the calcium phosphatereinforcement particles and the polymer particles.
 29. The method ofclaim 28, wherein the polymer particles are produced by dissolving thepolymer in a solvent under mixing, followed by precipitation or gelationof the polymer from the solution, followed by solvent removal.
 30. Themethod of claim 29, wherein the solvent removal is by way of vacuum ovendrying, distillation and collection, or freeze drying.
 31. The method ofclaim 26, wherein said providing the polymer includes providing a foamof polymer having continuous open porosity, and wherein saidco-processing includes infiltrating the polymer foam with a suspensionof the calcium phosphate reinforcement particles to form a preform. 32.The method of claim 31, wherein the polymer foam is produced bydissolving the polymer in a solvent under mixing, followed byprecipitation or gelation of the polymer from the solution, followed bysolvent removal.
 33. The method of claim 32, wherein the solvent removalis by way of vacuum oven drying, distillation and collection, or freezedrying.
 34. The method of claim 26, wherein said providing theanisometric calcium phosphate reinforcement particles includes providinga porous compact of the calcium phosphate reinforcement particles,wherein said providing the polymer includes providing a molten orsolvated polymer or as a polymerizing mixture comprising monomer andinitiator, and, optionally polymer powder, co-initator, and/orstabilizer, and wherein said co-processing includes infiltrating theporous compact of the calcium phosphate reinforcement particles with thepolymer.
 35. The method of claim 34, wherein the porous compact of thecalcium phosphate reinforcement particles is produced by dry pressingcalcium phosphate particles and sintering the dry pressed particles toform the compact.
 36. The method of claim 35, wherein the sintering isat a temperature of from about 600° C. to about 1000° C.
 37. The methodof claim 26, wherein said providing the polymer includes mixing monomerwith an initiator, and, optionally, polymer powder and co-initiator, toform a polymer-forming mixture, and wherein said co-processing includespolymerizing and hardening the mixture in situ.
 38. The method of claim37, wherein said initiator and/or co-initiator is selected from thegroup consisting of benzoyl peroxide, dimethylaniline, ascorbic acid,cumene hydroperoxide, tributylborane, sulfinic acid, 4-cyanovalericacid, potassium persulfate, dimethoxybenzoine, benzoic-acid-phenylester,N,N-dimethyl p-toluidine, dihydroxy-ethyl-p-toluidinebenzoyl peroxide,and any combination thereof.
 39. The method of claim 37, wherein saidmonomer is selected from the group consisting of methylmethacrylate(MMA), 2,2′-bis(methacryloylethoxyphenyl) propane (bis-MEEP), bisphenola polyethylene glycol diether dimethacrylate (bis-EMA), urethanedimethacrylate (UDMA), diphenyloxymethacrylate (DPMA),n-butylmethacrylate, tri(ethylene glycol) dimethacrylate (TEG-DMA),bisphenol a hydroxypropylmethacrylate (bis-GMA), and any combinationthereof.
 40. The method of claim 37, wherein said providing the polymerincludes adding a stabilizer to prevent premature polymerization of thepolymer.
 41. The method of claim 40, wherein said stabilizer is selectedfrom hydroquinone, 2-hydroxy-4-methoxy-benzophenone, or combinationsthereof.
 42. The method of claim 37, wherein said co-processingcomprises combining said anisometric calcium phosphate reinforcementparticles with said polymer-forming mixture prior to mixing thecomponents thereof.
 43. The method of claim 37, wherein saidco-processing comprises combining said anisometric calcium phosphatereinforcement particles with said polymer-forming mixture duringpolymerization.
 44. The method of claim 26, wherein the deforming and/ordensifying includes aligning the calcium phosphate reinforcementparticles morphologically and/or crystallographically.
 45. The method ofclaim 26, wherein the thermo-mechanically deforming and/or densifyingincludes channel die forging.
 46. The method of claim 26, wherein thethermo-mechanically or mechanically deforming and/or densifying includescompression molding or die pressing.
 47. The method of claim 26, whereinthe thermo-mechanically deforming and/or densifying includes injectionmolding.
 48. The method of claim 26, wherein the thermo-mechanicallydeforming and/or densifying includes extrusion or pultrusion.
 49. Themethod of claim 26, wherein the mechanically deforming and/or densifyingincludes the viscous flow of a molten or polymerizing polymer matrix.50. The method of claim 49, wherein the viscous flow is achieved bypercutaneous or surgical injection, channel die forging, compressionmolding, injection molding, or extrusion.
 51. The method of claim 26,further comprising adding a surface-active agent.
 52. The composite ofclaim 1, wherein the reinforcement particles are aligned in the matrixsuch that they have an orientation distribution function (ODF) ofgreater than 1 MRD.
 53. The composite of claim 52, wherein thereinforcement particles are aligned in the matrix such that they have anorientation distribution function (ODF) of at least about 3 MRD.
 54. Thecomposite of claim 53, wherein the reinforcement particles are alignedin the matrix such that they have an orientation distribution function(ODF) of about 5 MRD to about 20 MRD.
 55. A composite biomaterialcomprising: (a) a matrix including (i) a calcium phosphate compositionthat can cure in vivo, (ii) a thermoplastic polymer, or (iii) anycombination of (i) and/or (ii); and (b) anisometric calcium phosphatereinforcement particles dispersed within the matrix, wherein thereinforcement particles are aligned within the matrix and have anorientation distribution function (ODF) of greater than 1 MRD, andwherein the reinforcement particles have a mean aspect ratio (lengthalong c-axis/length along a-axis) of greater than 1 and less than 100.56. The composite of claim 55, wherein the mean aspect ratio is fromabout 5 to about
 50. 57. The composite of claim 55, wherein at leastsome of the reinforcement particles are shaped like whiskers.
 58. Thecomposite of claim 55, wherein at least some of the reinforcementparticles are shaped like platelets.
 59. The composite of claim 55,wherein the reinforcement particles are present in an amount of fromabout 1% by volume of the composite to about 60% by volume of thecomposite.
 60. The composite of claim 55, wherein the reinforcementparticles have dimensions of from about 1 micrometer to about 500micrometers along the c-axis and from about 0.02 micrometers to about 20micrometers along the a-axis.
 61. The composite of claim 55, wherein theanisometric calcium phosphate reinforcement particles are selected fromthe group consisting of amorphous calcium phosphate, biphasic calciumphosphate, calcium phosphate, dicalcium phosphate, dicalcium phosphatedihydrate, calcium hydroxyapatite, carbonated calcium hydroxyapatite,monocalcium phosphate, monocalcium phosphate monohydrate, octacalciumphosphate, tricalcium phosphate, alpha-tricalcium phosphate,beta-tricalcium phosphate, tetracalcium phosphate, and combinationsthereof.
 62. The composite of claim 55, further comprising at least oneadditive selected from the group consisting of growth factors,transcription factors, matrix metalloproteinases, peptides, proteins,and combinations thereof.
 63. A prosthesis for replacement of bonecomprising the composite of claim
 55. 64. A method of preparing thecomposite biomaterial of claim 55, the biomaterial comprising: (a) amatrix including at least one thermoplastic polymer and (b) anisometriccalcium phosphate reinforcement particles arranged within the matrix,said method comprising: providing the anisometric calcium phosphatereinforcement particles; providing the polymer; co-processing thepolymer and the calcium phosphate reinforcement particles to obtain asubstantially uniform mixture thereof; and thermo-mechanically ormechanically deforming and/or densifying the mixture to form thecomposite biomaterial.
 65. The method of claim 64, wherein saidproviding the polymer includes providing particles of the polymer in afirst suspension, wherein said providing the anisometric calciumphosphate reinforcement particles includes providing the reinforcementparticles (a) in the first suspension or (b) in a second suspension, andwherein said co-processing the polymer and the calcium phosphatereinforcement particles to obtain a substantially uniform mixturethereof comprises wet co-consolidating the calcium phosphatereinforcement particles and the polymer particles.